The P53 tumour suppressor protein is a central mediator of cellular stress response. P53 plays a major role in preventing tumour development. It responds to a range of potentially oncogenic stresses by activating protective mechanisms, most notably cell cycle arrest and apoptosis. Its importance as a tumour suppressor is reflected by its high rate of mutation in human cancer, with >50% of adult human tumours bearing inactivating mutations or deletions in the TP53 gene. In many cancers where p53 is wild-type, the p53 pathway may be altered by other oncogenic events. This means that the p53 response is probably defective in most cancers.
Contrary to the findings in solid tumours in adults, the occurrence of p53 mutations in virus-associated malignancies (e.g., cervical cancer), haematological malignant diseases and childhood cancer is very low. This may be the key to the much better prognosis of children with cancer compared to adults. When considering long term therapies or treatment of young patients, however, it is important to be aware of the mutagenic effects of many current therapies. Additionally, literature shows that treatment of B-CLL patients with DNA-damaging alkylating agents correlates with the appearance of mutations in p53 that are associated significantly with poor outcome and drug resistance. Improving the treatment of those cancers in which p53 function is not abolished by mutation may depend on finding novel non-genotoxic activators of the p53 response.
Many current anti-cancer therapies activate the p53 response via DNA damage. Non-genotoxic activation of the p53 pathway may open the way to long-term, including, prophylactic treatments for cancer. Molecules which are consistent with this requirement may be useful as therapeutic agents for the management of patients with hyperproliferative conditions, without abolishing p53 function by mutation.
It is an object of the present invention to provide molecules, and the use of those molecules, for the treatment and/or prophylaxis of conditions and diseases involving abnormal P53 function, such as hyperproliferative conditions, such as cancer, and related conditions.
It is a further object of the present invention to provide molecules, and the use of those molecules, for the treatment and/or prophylaxis of conditions and diseases associated with sirtuin expression and/or function, such as cancer, diabetes muscle differentiation, heart failure, neurodegeneration, aging, HIV infection and malaria.